Project Summary Obesity-related disorders account for 2.8 million deaths per year. The loss of circulating estrogen after menopause increases the prevalence of obesity and the risk of life-threatening, obesity-related disorders such as cardiovascular disease and stroke in women. Shift work and night-eating also increase the risk of obesity and metabolic syndrome suggesting that disruption of circadian rhythms causes metabolic dysfunction. This project will determine how estrogen interacts with the circadian system to protect females from obesity and related disorders. In our previous studies, we demonstrated a link between disruption of circadian rhythms, consumption of high-fat diet, and obesity in male mice. Male mice develop profound diet-induced obesity. We found that after only one week of high-fat diet consumption, the daily rhythm of eating behavior was immediately altered and the timing of the circadian clock in the liver was robustly advanced in male mice. In contrast, female mice are resistant to diet-induced obesity. In our preliminary studies, we found high-fat diet does not alter the daily rhythm of eating behavior or the liver clock in females. Thus, we hypothesize that retention of normal daily metabolic rhythms during high-fat diet consumption confers protection from diet- induced obesity in females. The goal of this proposal is to elucidate the molecular and behavioral mechanisms that protect daily rhythms from high-fat diet in females. Our specific aims are (1) to determine if estrogen regulates the effects of high-fat diet on daily rhythms in female mice; and (2) to determine if estrogen regulation of the daily rhythm of eating behavior protects females from diet-induced obesity. The completion of this project will reveal mechanisms whereby females are protected from diet-induced obesity and inform the development of novel therapeutics for obesity in women.